Cancer (malignant tumor) is one of the leading diseases threatening the human life today. The morbidity and mortality of cancers have increased sharply in recent years. The tumor development trend revealed by the World Health Organization indicated that, the annual global newly confirmed tumor patients were more than 10,000,000 since 1996. As of the end of 1996, the global total tumor patients had exceeded 40,000,000. Approximately 7,000,000 persons die of various cancers all around the world each year. In 2001, the world morbidity and mortality of tumor had increased by 22% from 1990. Cancer has become the second main cause of death just second to cardiovascular and cerebrovascular diseases. The most commonly seen cancers are lung cancer, breast cancer, colorectal cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, and bladder cancer. The authoritative survey data on the morbidity and mortality of cancers in China in 2006 published on the tenth National Clinical Oncology Conference showed that, the cancer deaths were 3,000,000 in China in 2006. There are approximately 2,120,000 newly confirmed cancer patients each year. Lung cancer is on the top of the mortality of malignant tumor. Experts estimated that, by 2020, the death toll will exceed 4,000,000; by 2025, tumor will become the first major cause for global death toll.
There are three means for clinically treating cancers: surgery, radiotherapy and chemotherapy. Antitumor drugs are the most commonly used way of the treatment. In 2008, the global market sale of antitumor drugs is US$ 48 billion. At present, clinical antitumor drugs are mainly classified into alkylating agent, antimetabolites, metal platinum, plant alkaloids and other crude drugs, cytotoxic antibiotics, etc. Platinum antitumor drugs are a sort of principal antitumor drugs and cisplatin was firstly developed in 1960s. The important difference from traditional cytotoxic antitumor drugs is their unique mechanism of action and excellent selectivity. The major target is DNA, which is cross-linked inter and intra DNAs and forms platinum complex˜DNA complex, to disturb DNA replication or combine with nucleoprotein and plasmosin, belonging to cell cycle nonspecific agent (CCNSA). Cis-dichlorodiamminoplatinum, i.e., Cisplatin, Cis-1,1-cyclobutanedicarboxylate platinum, i.e., Carboplatin, Cis-glycolic acid-diammine platinum i.e., Nedaplatin, oxalate-(trans-L-1,2-cyclohexyl diamine) platinum i.e., Oxaliplatin, Cis-[(4R,5R)-4,5-bi-(aminomethyl)-2-isopropyl 1,3-dioxane](bidentate) platinum, i.e., Sunpla, and 1,2 diaminomethyl-cyclobutane-lactate platinum i.e., Lobaplatin etc. have been successfully developed one after another. Platinum antitumor drugs are characterized by wide antitumor spectrum, good effect, etc. Moreover, they are well combined with other antitumor drugs. This not only improves the inhibition ratio of the existed tumor, but also expands antitumor spectrum, thus consolidating the position of platinum antitumor drugs in clinical treatment. In the ranking among hundreds of antitumor drugs conducted by the World Health Organization (WHO) in 1995, cisplatin ranks the second in the comprehensive evaluation on curative effect and market. Statistical data indicate that, among all chemotherapy regimens in China, more than 70%˜80% are dominated by platinum or compatible with platinum drugs.
Platinum antitumor drugs, however, now with high toxicity, have many defects, including bone marrow suppression, nephrotoxicity, nerve injury, etc., poor solubility, comparatively narrow anticancer spectrum, drug resistance, etc. Therefore, designing and synthesizing new platinum antitumor drugs remain one of the leading directions for the present antitumor drug research (M A Jakuper, M. Galanski, B. K. Keppler. Tumour-inhibiting platinum complexes-state of art and future perspectives, Rev. Physiol Biochem Pharmacol, 2003, 146, 1-53)
Substantive studies have been conducted in recent two years to reduce the toxic and side effects of platinum chemotherapy drugs, improve curative effect, reduce tumor recurrence and avoid drug resistance, and improve the water solubility of platinum compounds. For example, the solubility is 2.65 mg/ml for cisplatin, 7.9 mg/ml for recently developed Oxaliplatin, 17.8 mg/ml for Carboplatin, and 27 mg/ml for Minoplatin. Comparing with cisplatin, the toxic and side effects of Oxaliplatin and Carboplatin are reduced. The deficiency is that the solubility of above so-called water-soluble platinum compounds remains slight soluble or sparingly soluble. Murray A. Plan et al prepared the sodium alcoholate salt for platinum compounds, which effectively improved the solubility externally (U.S. Pat. No. 4,322,362A), but the compounds must be dissolved under the condition above pH10 and the toxicity has still not been effectively solved. Giulia C et al also prepared series of platinum compounds. However, the solubility of those compounds was still not remarkably improved (Chem Med Chem, 2009, 4(10), 1677-1685). WO2006091790A1 also made public a series of platinum compounds with specific structure, but similarly, the solubility was still not distinctively improved. Cycloplatinum synthesized by Russian Kurnakov Institute of Ordinary and Inorganic Chemistry is a cis-[S-(−) malate].ammonia.cyclopentylamino platinum (II), which can prolong the life of the animals that suffer from leukemia and hepatoma, without renal toxicity, and the myelosuppression is dose limited toxicity (S G Bagrova, Vopr Onkol, 2001, 47(6): 752756). American Bioscience, based on cycloplatinum, developed the compound coded as ADP, the chemical name was Cis-(2 amino succinato).(1S,2S-cyclohexyl diamine) platinum (II), displaying activity for traditional platinum anti-drug resistance (US Bioscience. Pharma Projects, 1998: a1744˜a1745). Although ADP has amino, the solubility remains lower; moreover, it cannot form salt with acid; the anti-tumor intensity is very weak and the toxicity is relatively great. Therefore, the existing technology still requires the platinum compounds with high solubility, less toxicity, and higher anti-tumor efficacy.